A combination of increasingly restrictive regulations and intensive public education campaigns over the past three decades has produced a dramatic reduction in smoking rates. Initial optimism about eradicating smoking, however, has given way to recognition that this strategy has resulted in an accumulation of smokers-around 25 percent of the population-who are differentially susceptible to the effects of nicotine and resistant to quitting. Although refractory smokers have been repeatedly shown to score high on measures of both nicotine dependence and a variety of cofactors, lack of definitive characterizations of these phenomena as they relate to smoking has hampered investigations of their relative contributions to the maintenance of smoking and difficulty in quitting. Evidence is now mounting, however, that more than one phenotype for smoking can be distinguished. The intent of the proposed research is to provide accurate identification and characterization of two important phenotypes by partitioning the effects of 1) nicotine dependence and 2) depression upon responses to nicotine and nicotine abstinence. Two main experiments will be conducted over a five-year period, using within-subject and between-group comparisons. In both studies, smokers will be classified into four groups based on combinations of dependence and depression, using the Composite International Diagnostic Interview to determine high or low nicotine dependence and the Center for Epidemiological Studies-Depression to determine diathesis for depression. In Experiment I, subjects will be tested for cue reactivity, withdrawal effects, and hedonic, physiological, and neuroendocrine response to nicotine after a brief period of enforced abstinence. They will then participate in a short term abstinence challenge following intensive exposure to motivational material created for public health campaigns, which will serve as a laboratory simulation of ability to stop smoking. In Experiment II, subjects will be pre-treated with the anti-depressant fluoxetine and then participate in the short-term abstinence challenge to determine whether relieving some of the symptoms of depression improves ability to abstain. Specification of phenotypic differences in high-risk smokers should shed light on current limitations of what once were successful public health strategies and suggest approaches that may be more appropriate to the needs of today's smokers; the proposed research will also generate phenotypic data on smoking that should be useful in directing future investigations of genetic mechanisms.